Brain and Muscle ARNT-Like 1 Ameliorates Sepsis-Induced Acute Lung Injury by Orchestrating Endoplasmic Reticulum-Phagy and Mitochondrial Metabolism.

Abstract

To evaluate the clinical prognostic value of the core circadian transcription factor brain and muscle ARNT-like 1 (BMAL1) in sepsis-induced acute lung injury (SI-ALI) and explore its mechanistic role in orchestrating organellar homeostasis and macrophage resilience. Prospective clinical cohort study and randomized blinded preclinical laboratory investigation. ICU and research laboratory of Renmin Hospital of Wuhan University. Thirty patients with SI-ALI and 12 healthy controls; adult male C57BL/6 mice and mouse alveolar macrophage cell line (MH-S) alveolar macrophages. Clinical monitoring of BMAL1, clock circadian regulator (CLOCK) genes, and hormones. Murine cecal ligation and puncture models, lipopolysaccharide treated MH-S cell treated with nobiletin, small interfering RNA-mediated knockdown of BMAL1, and pharmacological modulators of endoplasmic reticulum (ER)-phagy. Patients with SI-ALI exhibited profound circadian arrhythmia with significantly reduced expression of BMAL1 and CLOCK. BMAL1 levels were significantly lower in nonsurvivors and served as a robust predictor of 28-day mortality (area under the curve = 0.8177), showing a significant negative correlation with Sequential Organ Failure Assessment scores. In preclinical models, pharmacological activation of BMAL1 via nobiletin significantly mitigated lung histopathological damage, improved 5-day survival, and enhanced macrophage phagocytic and bactericidal activity. Mechanistically, BMAL1 deficiency impaired family with sequence similarity 134, member B-mediated ER-phagy, leading to inositol-requiring enzyme 1 increased and NADH:ubiquinone oxidoreductase core subunit V1, ATP synthase F1 subunit alpha, and seahorse-derived respiration/adenosine triphosphate production decreased. Nobiletin rescued these organellar defects in a BMAL1-dependent manner. BMAL1 is a master regulator of cellular homeostasis in SI-ALI. It protects against lung injury by orchestrating a coordinated response between ER-phagy and mitochondrial metabolism. BMAL1 represents a clinically valuable prognostic biomarker and a potential therapeutic target for SI-ALI.